In her student years, Metsola formed part of SDM (Studenti Demokristjani Maltin), KNZ (The National Youth Council) and MZPN (Moviment Zgħazagħ Partit Nazzjonalista), before being elected as Secretary General of the European Democrat Students (EDS - the student branch of the EPP), as well as to posts within the European Youth Forum (YJF). In 2002, she was elected vice-president of the Youth Convention on the Future of Europe which paved the way to her being closely involved in the negotiation and drafting of the European Constitutional Treaty and, later, the Lisbon Treaty.

Metsola successfully contested the casual election to fill in the vacated seat of Simon Busuttil on 24 April 2013, becoming one of Malta's first female Members of the European Parliament.[3] In parliament, she is a member of the European People's Party Group (EPP).

Metsola currently serves as vice-chair of the Committee on Petitions (PETI).[4] In addition, she contributes to and is a member of the following committees: the Special Committee on Organised Crime, Corruption and Money Laundering (CRIM), the Committee on Civil Liberties, Justice and Home Affairs (LIBE) and the parliament’s Delegation for relations with Albania, Bosnia and Herzegovina, Serbia, Montenegro and Kosovo (DSEE). In 2016, she joined the Parliament's Committee of Inquiry into Money Laundering, Tax Avoidance and Tax Evasion (PANA) that will investigate the Panama Papers revelations and tax avoidance schemes more broadly. She has also chosen to be a substitute member of the Committee on the Internal Market and Consumer Protection (IMCO), the Delegation for relations with Switzerland, Norway, the EU-Iceland Joint Parliamentary Committee and the European Economic Area (EEA) Joint Parliamentary Committee (DEEA) and the Delegation to the Parliamentary Assembly of the Union for the Mediterranean (DMED).

Currently listed in the "Mapping Reliable allies in the European Parliament (2014 – 2019)" document as being a 'Member of the 8th European Parliament likely to support Open Society values during the 2014–2019 legislature.' as a Coordinator for 'Committee on Civil Liberties, Justice and Home Affairs (LIBE)'

In her capacity as member of LIBE, Metsola led the EPP’s work on the non-binding ‘EU roadmap against homophobia and discrimination on grounds of sexual orientation and gender identity’ in 2014.[5] She co-authored a non-binding report on the European migrant crisis in 2016, aimed at establish a “binding and mandatory legislative approach” on resettlement and new EU-wide “readmission” agreements which should take precedence over bilateral ones between EU and non-EU countries.[6]